The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells.

Elena Perli (1, 2) , Carla Giordano (2) , Annalinda Pisano (2, 3) , Arianna Montanari (4, 2, 1) , Antonio F Campese (5) , Aurelio Reyes (6) , Daniele Ghezzi (7) , Alessia Nasca (7) , Helen A Tuppen (8) , Maurizia Orlandi (2, 5) , Patrizio Di Micco (9) , Elena Poser (9) , Robert W Taylor (8) , Gianni Colotti (10) , Silvia Francisci (4, 1) , Veronica Morea (10) , Laura Frontali (4, 1) , Massimo Zeviani (6) , Giulia d'Amati (2, 1)

1 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti
2 Department of Radiology, Oncology and Pathology
3 Department of Internal Medicine and Medical Specialties
4 Department of Biology and Biotechnology "Charles Darwin"
5 Department of Molecular Medicine
6 MRC - Mitochondrial Biology Unit
7 Unit of Molecular Neurogenetics
8 Wellcome Trust Center for Mitochondrial Research
9 Department of Biochemical Sciences "Rossi Fanelli"
10 CNR | IBPM - CNR Istituto di Biologia e Patologia Molecolari [Roma]

Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNA(Ile) gene. Importantly, we further demonstrate that the carboxy-terminal domain of human mt leucyl-tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with these "mild" mutations or with the "severe" m.3243A>G mutation in the mt-tRNA(L)(eu(UUR)) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNA(Leu(UUR)) with high affinity and stability and, with lower affinity, with mt-tRNA(Ile). Taken together, our results sustain the hypothesis that the carboxy-terminal domain of human mt leucyl-tRNA synthetase can be used to correct mt dysfunctions caused by mt-tRNA mutations.

Mots clés: aminoacyl-tRNA synthetases; mitochondrial disease; mitochondrial tRNA mutations; molecular therapy Subject Categories Genetics; Gene Theraphy & Genetic Disease

Domaines: Génétique; Biochimie, Biologie Moléculaire

Elena Perli, Carla Giordano, Annalinda Pisano, Arianna Montanari, Antonio F Campese, et al.. The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells.. EMBO Molecular Medicine, 2014, 6 (2), pp.169-82. ⟨10.1002/emmm.201303198⟩. ⟨pasteur-01168181⟩